1. Field of the Invention
The present invention relates to a movement disorder monitor, and a method of measuring and quantifying the severity of a subject's movement disorder and symptoms thereof. The present invention additionally relates to a development system, and a treatment and drug delivery system for dosing a subject in response to changes in severity of a subject's symptoms.
2. Technical Background
Movement disorders include, but are not limited to, Parkinson's disease (PD), essential tremor, dystonia, and Tourette's syndrome. Such disorders present a multitude of symptoms affecting a person's daily life, those symptoms include tremor, bradykinesia, rigidity, gait/balance disturbances, dyskinesias, and the like. The treatments can involve pharmaceutical interventions, fetal cell transplants, surgery, or deep brain stimulation in some of these disorders. The efficacy of these interventions is often judged by the intervention's ability to alleviate subject symptoms and improve their quality of life. With Parkinson's disease for example, the major symptoms that affect quality of life are tremor, bradykinesia, rigidity, and dyskinesia. These symptoms are partly responsible for the subject's functional disability and social embarrassment.
Tremors are involuntary muscle contractions characterized by oscillations of a body part. Tremor of the hands can be cosmetically upsetting and affect functional tasks such as grasping of objects. Resting tremors usually occur at frequencies of approximately 4-7 Hz while the frequency of action of postural tremor is higher, usually between 9-11 Hz. Tremor is a symptom often targeted by treatment. The standard clinical method for analyzing rest and postural or action tremor is qualitative assessment by a clinician and assignment of a score.
Bradykinesia refers to delays or hesitations in initiating movements and slowness in executing movements. The standard clinical method for analyzing bradykinesia is qualitative assessment by a clinician and assignment of a score. This score is assigned while the subject completes a repetitive finger-tapping task, a repetitive hand opening-closing task, and a pronation-supination task. Objective assessment by this means is difficult and variable. It has been found that movement rate and time are useful in better characterizing bradykinesia.
Rigidity occurs because muscles of the body are overly excited. The neurons involved in inhibition circuitry have died due to Parkinson's disease and muscles may receive continuous excitation. Rigidity causes the joints of the subject to become stiff and decreases range of motion. During normal movement, an agonist muscle contracts while the antagonist muscles relax. However, due to the constant motor unit input, the antagonist is unable to relax. Again, the standard clinical method for analyzing rigidity is qualitative assessment by a clinician and assignment of a score. To do so a clinician passively moves the subject's joints through a range of motion while the subject relaxes.
Dyskinesia is one of the most common and disabling complications of chronic drug therapy. Dyskinesias are wild involuntary movements that typically occur when the benefit from the drug therapy is at its maximum. Clinical assessment of dyskinesias typically relies on self-reporting by the subject. There is a great need to objectively quantify these involuntary movements in view of the growing number of pharmacologic agents and surgical procedures to improve dyskinesia.
While standard clinical evaluation involves qualitative assessment of these to symptoms, recently some efforts have been made to quantify symptoms of movement disorders. Accelerometers and gyroscopes have been used individually to quantify some of these movement disorder symptoms, however, alone each sensor has limitations. Accelerometers operate in response to the local gravitational field; therefore they often have problems in separating changes in linear acceleration from rotation. Further, results of a second integration required to obtain linear position are often contaminated with noise, making measurement difficult at best. Gyroscopes measure angular velocity independent of gravity with a good frequency response; however, static angular position cannot be measured accurately due to DC drift characteristic with these devices. Combining the information from both accelerometers and gyroscopes can provide a more accurate method of quantifying motion.
With the tremendous amount of research into neuroprotective treatments designed to slow the progression of movement disorders, and particularly Parkinson's disease, the need for standardized, highly sensitive assessments of movement disorder treatments cannot be understated. Large-scale clinical drug trials for medication and drug treatment methods often involve dozens of sites and thousands of subjects located all over the world. Outcome measures are typically in the form of a single clinical assessment completed at weekly or monthly intervals. These clinical assessments can suffer from bias, placebo effects, limited resolution, and poor intra- and inter-rater reliability.
Currently, no commercially available system provides a means to objectively quantify the severity of movement disorder symptoms in real-time. Furthermore, many of these systems are bulky and cannot easily be worn by a subject during normal daily activities so as a result can only be used to monitor the subject in an intermittent fashion. In addition, some of these systems are tethered, which reduces subject safety, limits home monitoring capabilities, and does not allow for recording of some movement disorder symptoms. Finally, none of the current systems have clinician interface software, which quantifies symptoms such as tremor, bradykinesia, rigidity, and dyskinesias and relates them to standard rating scales such as the Unified Parkinson's Disease Rating Scale (UPDRS). Additionally, none of these systems have clinical video instruction and real-time clinical video feedback.
Even further, the currently available systems are typically hindered by a large degree of variability in the quantification of symptom severity. This is due in large part to the subjective nature of scoring systems, such as the UPDRS, which require clinician observation of the subject and/or movement data, and/or subject feedback regarding their subjective evaluation of the severity of symptoms. Systems requiring subject feedback, for example by use of a journal for recording the subject's perception of symptoms throughout the day, suffer from a lack of subject compliance. Many subjects provide skewed information, or more often fail to comply with the reporting standards completely and then fill in the journal near to the time of an appointment with the clinician, rather than on a daily basis as the symptoms occur (or do not occur). Even systems which rely in part or completely on scoring of clinicians or other trained personnel offer a high degree of variability due to the need for subjective observation or reporting of the severity of symptoms. Different clinicians might score a given observation differently, and the same clinician might score the same observation differently if presented with the data at different times. This variability and subjectivity can prevent an accurate quantification of symptom severity which may lead to inappropriate treatment of the subject including under or over medication. This variability and subjectivity further hinders the research and development process requiring long periods of time and large numbers of subjects in order to verify and qualify new treatment methods for clinical use.
Measurement errors can take the form of inconsistencies caused by the participant's physical or mental condition, variations in the testing procedure, or to tester error. Additionally, subjects may perform better or more consistent on a task due to learning effects rather than as a result of the therapy being studied. Various methods to improve consistency such as using the same rater or testing on the same time of day can improve reliability; however, most of these techniques are not practical for large, multi-center clinical trials.
As an example, the most common outcome measure in Parkinson's Disease drug trials, the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS Section III), requires a clinician to qualitatively rate various motor symptoms on a 0-4 integer scale while viewing the subject performing tasks. While studies have shown relative high test-retest reliability for the UPDRS-III as a whole (see e.g., Teresa Steffen et al, Test-Retest Reliability and Minimal Detectable Change on Balance and Ambulation Tests, the 36-Item Short-Form Health Survey, and the Unified Parkinson Disease Rating Scale in People with Parkinsonism, 88 PHYSICAL THERAPY 733 (Jun. 1, 2008)), this traditional method of subject evaluation presents several problems for large scale pharmaceutical studies. The required presence of a trained clinician to rate symptoms creates costs associated with subject travel and clinician time. In addition, the use of medications for treatment of Parkinson's Disease often causes symptom fluctuations during the day, which cannot be monitored during a single visit with the trained clinician. To compensate for this lack of temporal resolution, subjects are often asked to complete daily diaries; however, in clinical trials, these diaries are notoriously poor in quality as subjects may have a tendency to wait and fill out the diaries in retrospect rather than throughout the day on a daily basis. Also, clinical trials typically employ several clinicians at different sites, which may lead to symptom scoring variability and in turn decreased sensitivity due to the subjective observations of each clinician. Finally, the discrete nature of the integer scores (0, 1, 2, 3, or 4) under the UPDRS does not allow for the high sensitivity measurements that would be necessary to capture the very subtle changes that might occur during a neuroprotective drug trial. Neuroprotective drugs target subjects with early Parkinson's Disease when symptoms are still very mild (correlating to a 0 or 1 score on the UPDRS). Evaluation of neuroprotective therapies can take years or even decades due to the long period before a UPDRS measurable response is seen.
Many researchers have cited the inability to measure slight changes in motor symptom severity using the UPDRS as a hurdle in evaluating potential neuroprotective agents. And while reliability of the UPDRS-III (the motor section) as a whole may be high, specific symptoms or items, such as those related to bradykinesia for example, lack specificity and suffer from poor intra- and inter-rater reliability. For rating tremor, the Movement Disorders Society (MDS) revision of the UPDRS tremor scoring guidelines specify amplitude ranges in centimeters that correspond to a 0-4 score (see C. G. Goetz et al., Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results, 23 MOV. DISORD. 2129 (Nov. 15, 2008)); however, it is difficult, if not impossible, to judge tremor amplitude precisely by visual observation alone. Even if precise visual observations were possible, converting a wide range of amplitudes to an integer score greatly reduces resolution. For evaluating finger tapping, hand movements, and pronation-supination, evaluations are even less reliable since raters must account for speed, amplitude, rhythm, hesitations, freezing, and fatigue, all with a single score. In a study designed to test inter-rater reliability, the UPDRS finger tapping task, the most widely used measure of bradykinesia, was misclassified by 70.6% of the 54.6% of clinicians who failed their first rating (see C. G. Goetz and G. T. Stebbins, Assuring interrater reliability for the UPDRS motor section: utility of the UPDRS teaching tape. 19 MOV. DISORD. 1453 (2004)). As for intra-rater reliability, two studies showed only poor to fair agreement in bradykinesia ratings (see D. A. Bennett et al., Metric to properties of nurses' ratings of parkinsonian signs with a modified Unified Parkinson's Disease Rating Scale, 49 Neurology 1580 (1997); see also R. Camicioli R et al., Discriminating mild parkinsonism: Methods for epidemiological research. 16 MOV. DISORD. 33 (2001)). A third study showed fair to good agreement; however, raters were not blinded and the subjects had early, untreated PD, which restricts the range of test-retest reliability (see A. Siderowf et al., Test-retest reliability of the unified Parkinson's disease rating scale in patients with early Parkinson's disease: results from a multicenter clinical trial. 17 MOV. DISORD. 758 (2002)). Recently, the modified bradykinesia rating scale (MBRS) was introduced for independently rating the bradykinesia manifestations of speed, amplitude, and rhythm. Each manifestation is given an integer score from 0-4 during finger-tapping, hand movements, and pronation-supination tasks. The MBRS has similar inter- and intra-rater reliability to that of the UPDRS and was found to be more sensitive than the UPDRS in identifying how different aspects of bradykinesia respond to medication, highlighting the need for more sensitive assessment of bradykinesia. While an improvement, the MBRS is still a subjective scale with limited (whole number: 0, 1, 2, 3, or 4) resolution, cannot be captured without a clinician present, and has inter- and intra-rater reliability issues similar to the UPDRS (see D. A. Heldman DA et al, The modified bradykinesia rating scale for Parkinson's disease: Reliability and comparison with kinematic measures, 26 MOV. DISORD. 1859 (2011).
It is therefore an object of the present invention to provide a system for accurately quantifying symptoms of movement disorders. It is still another object of the present invention to provide a system that accurately quantifies symptoms utilizing both kinetic information, and in some embodiments electromyography (EMG) data. It is further an object of the present invention to provide accurate, reliable, repeatable quantification of movement disorder symptoms allowing for reduced time and cost in development, and more rapid and accurate treatment of subjects. It is still another object of the present invention to provide a wireless movement disorder system that can be worn continuously to provide continuous information to be analyzed as needed by the clinician, though need not be, and may preferably not be worn continuously. It is still further another object of the present invention to provide a movement disorder system that can provide analysis in real-time. It is a further object of the present invention to provide a movement disorder symptom quantification system that can automatically and immediately make data and the provided analytical information available for further analysis and review in real-time. It is still further another object of the present invention to provide a movement disorder system to allow for home monitoring of symptoms in subject's with these movement disorders to capture the complex fluctuation patterns of the disease over the course of days, weeks or months. It is still further an object of the present invention to maximize subject safety. It is still further an object of the present invention to provide a system with clinical video instruction and real-time clinical video feedback. It is still further an object of the present invention to provide a treatment delivery system that can monitor symptoms in subject's and deliver treatment in response to those symptoms. Finally it is the object of the present invention to provide remote access to the clinician or physician.